Neuroblastoma Power Notes [1]

Where do neuroblastic tumors (NBT) arise from?
They arise from the sympathetic cells of the neural crest. Thus NB can occur in sympathetic ganglia, sympathetic para-ganglia, or adrenal gland.

How is NB differentiated from other small round blue cell tumors?
The histopathologic findings characteristic of NB are:
1. Rosettes: NB cells surrounding neural fibrils
2. Neuropil: neuritic processes
3. Schwannian cell stroma: reactive/non-neoplastic tissue, recruited by tumor cells, and composed mostly of sheets of spindle cells. Schwannian stroma has an antineoplastic/anti-angiogenic/pro-differentiating effect on NB cells. The amount of stroma present is the major factor that divides neuroblastic tumors into NB vs. ganglioneuroblastoma and ganglioneurooma. More Shwannian stroma imparts better prognosis

What is the Shimada classification and what is it based on?
The Shimada classification is an age-linked histopathologic classification that is used to divide neuroblastic tumors in to favorable and unfavorable histology groups. It depends on
1. Degree of cellular differentiation
2. Mitotic-Karyorrhectic index: Number of cells in mitosis or Karyorrhexis (cell death) per 5000 cells. MKI can be low (<100), intermediate (100-200), or high (>200).
3. age
4. Amount of Shwannian stroma
The Shimada classification has independent prognostic value, where FH tumors have a 90% 5 year EFS, and UH tumors have a 30% 5 year EVS.

How is the International Neuroblastoma Pathologic Classification (INPC) different from the Shimada classification?
The INPC is based on the Shimada classification. It divides neuroblastic tumors into 4 tumor categories under 2 distinct prognostic groups: favorable subgroup (FS) and unfavorable subgroup (US).
FS:
Ganglioneuroma differentiating
Ganglioneuroblastoma intermixed type
Ganglioneuroblastoma nodular (with specific favorable features)
US:
Ganglioneuroblastoma nodular (unfavorable features)
Neuroblastoma

What is the histopathologic definition of NB?
NB is a Shwannian poor neuroblastic tumor (<50% Schwannian stroma) divided into three main types 1. Undifferentiated: No neuropil present 2. Poorly differentiated: <5% cells showing signs of differentiation into ganglion cells and neuropil present 3. Differentiating: >5% cells showing signs of differentiation and neuropil present

What defines Ganglioneuroblastoma (GNB) and Ganglioneuroma (GN)?
GNB and GN are both Schwannian stroma rich neuroblastic tumors (>50%)

What are the characteristics of GNB?
GNB cells are progressing into mature ganglion cells with >50% of cells in the maturing form (not completely mature, otherwise would be ganglioneuroma). GNB has residual foci (vs scattered) of neuroblastic cells that constitute <50% of cells. GNB is divided into the intermixed type (GNB-I) (where the foci of neuroblastic cells are microscopic) and the nodular type (GNB-N) (where foci are macroscopic) The GNB-I type are considered under the favorable subgroup while the GNB-N can be either favorable or unfavorable subgroup based on INPC factors [2] What are the characteristics of GN?
GN divided into GN mature (composed of mature cells and no neuroblastic elements) and GN maturing. The GN-maturing contains scattered (vs. foci) differentiating neuroblastic cells. Unlike GNB, these cells do not form distinct foci.

What is Horner's syndrome?
Horners syndrome results from loss of sympathetic innervation to part of the face. It consists of:
1. Ptosis: drooping of the eyelid due to loss off innervation of the upper tarsal muscle
2. Mioisis: small pupil
3. Anhydrosis: Decreased sweating on the affected side of the face
4. Enphthalmos: Impression that the eye is sunken
5. Heterochromia (in children): due to decreased melanin pigment deposition in the pupil on the effected side, secondary to loss of sympathetic innervation

What is acute cerebellar ataxis?
Also referred to as the 'dancing eyes syndrome', usually occurs in infants with mediastinal masses and results from excessive catecholamine production
It consists of:
1. Myoclonus: brief, involuntary twitching of muscles
2. Opsoclonus: uncontrolled eye movement
3. Nystagmus

Where are NB's usually found?
Adrenal gland (50%), Paraspinal ganglia (25%), Thorax (20%), pelvis (4%), and neck (1%)

Where does NB metastasize to?
40% of NB are stage 4 (metastatic) at time of diagnosis. Metastasis is most frequently to bone (bone pain), Bone marrow (anemia), and lymph nodes.
Raccoon eyes result from retrobulbar venous plexus spread.

What is stage 4S NB?
A specific type of metastatic NB found in infants (<1 year). Primary tumor is localized (stage 1, 2A, or 2B) and spread is limited to: 1. Skin: blueberry muffin lesions 2. Liver: can cause respiratory distress from hepatomegaly 3. Bone marrow: malignant cells should be limited to <10% nucleated cells. Can cause anemia. What are the different options for diagnosis of NB?
1. Histopathology of primary tumor OR
2. Tumor cells in bone marrow + elevated urine catecholamines

What laboratory values correlate with NB tumor burden?
1. LDH
2. Catecholamines
3. Neuron specific enolase
4. Ferritin

How often are calcifications found on CT scan?
85% of cases

In what setting is MRI better than CT scan for NB imaging?
1. evaluation of stage 4 disease: Bone and bone marrow metastatic disease
2. evaluation of encroachment into neural foramen
3. evaluation of vessel encasement

What is MIBG scan and how does it work?
MethIodoBenzylGuanine is taken up by the storage granules in chromaffin cells, in the same way catecholamines are. Detects the primary tumor, involved LN's, and metastatic disease.

What is the main drawback of INSS and how is that counteracted?
The main drawback is the the staging and thus the prognosis is dependent on extent of resection, and thus the skill and aggressiveness of the surgeon. Image defined risk factors, those that preoperatively predict worse prognosis, can help provide a more uniform system for staging disease at presentation.Such factors include vessel encasement, extension into neural foramena etc...

What are the two main categories of determinants of prognosis?
1. Clinical factors: age and stage
2. Biological factors: NMYC, DNA plyody (in infants), histopathologic classification (Shimada)
additional variables include LOH: 1p or 11q deletions. Loss of tumor suppressor genes. Used to define duration of chemotherapy in some situations.

What is the probability of 5 year disease free survival?
Low risk group > 95%
Intermediate risk group > 90%
High risk group < 30% What role does partial tumor resection play in NB?
As long as there is no N-MYC amplification, >50% resection of localized tumors (including stage 2 disease) keeps patients in the low risk group.

What is the adjuvant therapy for low risk disease?
Low risk disease is observed after resection, except in the situation where less than 50% of the tumor was resected or in the presence of organ or life threatening symptoms.

When is 4S disease considered intermediate risk?
when symptomatic, has unfavorable biologic characteristics (by Shimada/INPC) or DNA index=1, or when no tissue is obtained for evaluation.

What chemotheraputic agents are used for intermediate risk disease?
cyclophosphamide, doxorubicin, carboplatin, etoposide.
Patients with favorable histology receive 4 cycles, unfavorable histology receive 8 cycles (each three weeks apart).

What is the current COG protocol goal for intermediate risk NB?
Protocol ANBL0531: Aims at reducing chemotherapy by decreasing the number of cycles.

What are the main chemotherapy strategies for high risk NB?
1. combination of agents to decrease resistant tumor growth and improve synnergy
2. use of maximal tolerated dose/high dose intensity
3. Target therapy for minimal residual disease
for autologous BM transplant, cells are harvested after second cycle of chemotherapy.
after neo-adjuvant therapy, resection re-evaluated after 5th cycle

What is the current COG protocol for high risk NB?
Protocol ANB0532: looks at role of further intensification of myoablative therapy, effect of radiation on residual and metastatic disease, test the effect of dose-intensified topotecan containing induction therapy.

How is response to therapy assessed?

1. volume (radiologic)
2. urine catecholamine levels
3. MIBG scans

Who are the patients who undergo surgical therapy alone without adjuvant therapy?

Most localized tumors with favorable histology:
stage 1 tumors
stage 2 A/B with no N-MYC amplification and >50% resection
stage 3 midline tumors completely resected with negative nodal disease

When is LN assessment not important in NB?

LN involvement in thoracic neuroblastoma does not affect risk classification, despite potential effect on staging

References: (Ashcraft textbook unless otherwise specified):
1. Ashcraft's Pediatric Surgery. 5th Edition. Chapter 68: Neuroblastoma
2. Okamatsu et al. Clinicopathologic characteristics of ganglioneuroma and ganglioneuroblastoma: A report from the CCG and COG. Pediatr Blood Cancer (2009) 53:563-9

4 mechanisms of esophageal injury by button batteries

Coins, the most commonly encountered ingested foreign body in children, cause complications related to chronic impaction and erosion. Button batteries are more dangerous. Methods by which they can cause damage (mostly when stuck in the esophagus) include

1. Toxic effect of mercuric oxide: some batteries contain lethal levels of mercuric oxide (5g). Batteries containing other heavy metals, lithium, or manganese are not toxic.
2. Electrical discharge from the battery
3. Pressure necrosis (as with coins)
4. Caustic injury from leakage of the battery's contents

Interestingly, batteries smaller than 1.6cm in diameter do not get lodged in the esophagus. Restricting the size of batteries produced to less than 1.6cm may help prevent serious injuries that can occur in as little as 5 hours after ingestion.

Reference:
Yardeni et al. Severe esophageal damage due to button battery ingestion: can it be prevented?
Pediat Surg Int (2004) 20:496

Variation in resource utililization associated with the management of appendicitis in children (APSA2011)

This presentation shed light on the spectrum of hospital costs entailed by different institutions for a somewhat uniform disease process, simple appendicitis, and the more heterogenous form, complicated or perforated appendicitis.

Not surprizingly, the authors found a significan variation in resourse utilization between institutions. This included the use of imaging studies and laboratory tests, readmission rates for both simple and complicated appendicitis, and hospital costs. Most strikingly, the authors noted an adjusted, case-related hospital cost for simple appendicitis that ranged from $4,000 to $10,000. As to complicated appendicitis, the cost ranged from $6,000 to $27,000.

Despite the limitation of studies obtained from databases, and the lack of correlatio between resource utilization and outcome, this study highlights the marked variability in management of a common condition that results in substantial resource utilization.

Why does simple appendicitis cost $4K in one hospital and $10K in another. Is the answer as simple as using cheaper but equally effective instruments? And if so, should we not all be standardizing this operation to help save what seems to me to be a lot of money?

Reference:
Variation of resource utilization associated with the management of appendicitis in children: implications for quality improvement through comparative analysis and collaborative networking.
Rangel SJ, Baxter J, Barnes J.

A bowel prep is not necessary before colosotmy reversal in kids (APSA 2011)

In this retrospective study looking at data from three institutions, the authors compared LOS and complication rates after colostomy takedown between pediatric patients who underwent a mechanical bowel prep and those who did not.

When they reviewed the data from 272 children (187 underwent a prep) they noted a longer hospital LOS for the prep group (5.6 vs 4.4 days); 122 of them had been pre-admitted for the prep. They also noted a higher rate of wound infections for the prep group (14.4 vs 5.8%). No significant difference was noted in the rate of abdominal abscess formation, anastomotic leaks, or C-diff infections.

Despite the limitations of this retrospective study, which may be comparing individual surgeon outcomes rather than the effect of bowel preps, this is another nail in the coffin of the pre-op bowel prep dogma that will hopefully be sealed by a PRS by the same group.

Reference:
A multi-center evaluation of the role of mechanical bowel preparation in pediatric colostomy takedown.
Serrurier K, Liu j, Breckler F, et al.

What's the Pediatric Appendicitis Score (PAS) and is it actually helpful?

So who hasn't received the call for a kiddo with 'classic' appendicitis only to see the kid and send him home because he's constipated.

What if there was a consistent and reliable way of communicating the "classic'ness" of someone's abdominal pain between healthcare workers; NP from an outside hospital calling for a transfer or ED physician calling for a surgical consult.

Enter PAS.

The PAS was introduced by Maden Samuel in 2002 as a way to stratify children's risk of having appendicitis when they present with abdominal pain. The scoring system consists of 8 findings (6 worth 1 point, and 2 worth 2 points for a total score of 10 points). Since Samuel's inception, several studies have addressed the sensitivity and specificity of this scoring system and attempted to develop strategies for it's use, mostly in deciding whom to take to the OR without imaging, whom to image, and whom to send home.

Goldman et al from Sick Kids in Toronto prospectively tested the PAS on unselected children with abdominal pain. Based on the scoring system, they noted that if they had sent kids with a score less than or equal to 2 home, there would have been a 2.5% missed appendicitis rate. on the other hand, if they took anyone with a score greater or equal to 7 to the OR, the rate of negative appendectomies would have been 4%.

Another study by Bhatt et al looked at the use of PAS on children suspected of having appendicitis and noted that sending home children with a PAS of 4 or less would have resulted in a missed appendicitis rate of 2.4%, while operating on those with a PAS greater or equal to 8 would have resulted in a negative appendectomy rate of 8.8%.

Reading through the papers, it is clear that the PAS is not perfect. What about the female who is mid cycle and has severe, sudden onset abdominal pain, nausea, and right lower quadrant tenderness. I wouldn't take her to the OR without imaging even if her score was 10/10. Clearly there's an important role of the "intangible ingredient" in patient evaluation, and no scoring system could take the place of a thorough history, exam, and experience. What the PAS does do is help standardize the way we communicate the level of suspicion for appendicitis, and may have a role in developing pathways to help physicians decide on whom to image, and whom not to, before a surgical consult is called.

So instead of 'classic' appendicitis (which clearly means different things to different people), a phone call about a patient with PAS of 8 would probably be much more meaningful to all parties involved.

References:

Maden S. Pediatric appendicitis score. Journal of Pediatric Surgery 2002;37:877

Goldman et al. Prospective validation of the pediatric appendicitis score. Journal of Pediatrics 2008;153:278

Bhatt et al. Prospective validation of the pediatric appendicitis score in a Canadian pediatric emergency department. Academic Emergency Medicine 2009;16:591

What to do with a 2 YO in a C-collar?

Again, I find myself in the situation where I have to call the neurosurgery resident to evaluate a toddler in a C-collar because she keeps crying every time I touch her; making her exam unreliable. Thinking he's going to get a flex-ex, I find out that he cleared her clinically. Am I missing something?

Some basic questions to help solve this problem. First, what's the rate of C-spine injury (CSI) with or without spinal cord (SC) involvement in the setting of blunt trauma in this age group? Second,in which kids should I be worried about a CSI? Third, when are imaging studies indicated? Finally how do we clear the c-spine in a non-verbal child (whether imaging done or not)?

Polk-Williams et al reviewed the National Trauma Data Bank and identified over 95 thousand children younger than 3 years who sustained blunt trauma. The overall rate of CSI was 1.6%, with most injuries occurring in the setting of MVC's (rate of CSI doubles to 3.2%). Overall rate of SC injury (with or without a spinal column injury) was 0.4%. As expected most CSI (66%) occurred in the setting of MVC's, the second most common mechanism was falls (15%).

Ok, so CSI are uncommon, but occur more frequently with MVC (logical). But what do I do with this girl who fell off a trampoline? She has a GCS of 15, no distracting injuries, a relatively non-worrisome mechanism, but still cries every time I get close?

A multi center study of the American Association for the Surgery of Trauma looked at children younger than 3 years of age who sustained blunt trauma to clarify the approach to C-spine clearance (rate of CSI in that study was 0.66%). Based on predictors of CSI, they devised a weighted score that can be used to stratify kids based on risk for CSI and thus help determine who needs imaging and who doesn't. The score includes GCS<14 (3 points), GCSeye=1 (2 points), MVC (2 points), age 2 years or older (1 point). Based on the study, a score of 0 or 1 corresponded to a negative predictive value for CSI injury of 99.9%, and these children may be cleared without imaging studies. 70 percent of the population they studies fell into this category. Importantly, the few who escaped capture by this scoring system had other signs that prompted radiologic evaluation (splinting of neck and evidence of substantial head trauma). So based on that data, my girl in the ED, who had her eyes (and lungs) spontaneously wide open, could have been cleared without C-spine xrays. Which is fine, but I still needed to do an exam. Which is where I still am not sure that a screaming kid could have been cleared clinically. So, although based on these numbers, the chance of this girl having a CSI is minute, I'm not sure I would be comfortable clearing her C-spine without a good physical exam. References:

Polk-Williams A. et al. Cervical spine injury in young children: a National Trauma Data Bank review. Journal of Pediatric Surgery (2009). 43(9):1718-21

Pieretti-Vanmarcke R. et al. Clinical clearance of the cervical spine in blunt trauma patients younger than 3 years: A multi-center study of the American Association for the Surgery of Trauma. The Journal of Trauma (2009). 67(3):543-550

Laparoscopic repair of inguinal hernias in female children: the Inversion/ligation technique

The open repair for inguinal hernias in children is a time honored technique used by most pediatric surgeons. Different variations of laparoscopic repair techniques have been adopted by some pediatric surgeons, with the main criticism of those techniques being a high rate of recurrence (4% compared to 1% with the open repair).

Despite my overall skepticism with laparoscopic repair techniques and their outcome, one particular version used for repair of hernias in females is quite appealing.

The inversion-ligation technique for repair entails passing a laparoscopic grasper into the inguinal canal through the internal ring, grasping the distal aspect of the sac, and inverting it into the abdomen. The inverted sac is then twisted and doubly ligated with an endo-loop.

Lipskar et al looked at the outcome of 173 girls who underwent a total of 241 hernia repair operations. The mean age was 5 years. One third of patients were found to have a contralateral patent processus vaginalis/hernia. All were successfully repaired in an average time of 40 minutes and 90% were discharged home the same day. Recurrence rate was 0.8%.

The appealing part of this operation is that, unlike other laparoscopic hernia repair techniques, the hernia sac is not left within the canal, which may be a major contributor to the reported high recurrence rate in other techniques. Because of the absence of any important structures (vas etc..), the hernia sac in girls can be bluntly pulled off the round ligament and inverted.

Lipskar et al. Laparosocpic inguinal hernia inversion and ligation in female children: a review of 173 consecutive cases at a single institution. Journal of Pediatric Surgery (2010) 45,1370-1374